AVO Triplet Regimen Continues to Show Durable Responses in High-Risk CLL

The triplet regimen acalabrutinib (A; Calquence), venetoclax (V; Venclexta), and obinutuzumab (O; Gazyva; AVO) in the frontline chronic lymphocytic leukemia (CLL) setting was highly active and well tolerated demonstrating durable responses at a median follow-up of 35 months and a progression-free survival (PFS) rate of 93% in a phase 2 trial (NCT03580928). However, patients with TP53-aberrant disease did not respond well and represent a continuing unmet need.

Findings were presented by Catherine C. Coombs, MD, associate professor, Department of Medicine, University of California, Irvine, during the Oncology Town Hall™: Primary Investigators Present Key Abstracts in the Management of CLL meeting, sponsored by PER® (Physicians’ Education Resource®, LLC).¹

Historically, novel-agent triple regimens have been highly active in CLL, with Rogers et al² demonstrating that the combination of obinutuzumab, ibrutinib (Imbruvica), and venetoclax resulted in deep remissions in findings from the CLL2-GIVe trial (NCT02758665).³ Data showed that 78.0% of patients had undetectable minimal residual disease (uMRD) in peripheral blood (PB) and 65.9% of patients had uMRD in bone marrow (BM). Estimated PFS and overall survival (OS) rates at 24 months were both 95.1% in that study.³ The AVO regimen was also explored previously by Davids et al,⁴ in a study (NCT03580928) whose data showed that uMRD in the BM merited further investigation. In this study, BM uMRD rates were similar regardless of TP53 status.

Treatment-naïve patients with CLL were enrolled in the all-comers portion (n = 37), which was followed by a multicenter expansion that was restricted to patients with TP53-aberrant disease (n = 31). Cycle 1 consisted of 100 mg of acalabrutinib twice a day for 28 days, followed by 2 cycles of acalabrutinib plus obinutuzumab at 100 mg. In cycle 4, day 1 (C4D1), venetoclax was introduced at 20 mg, then 50 mg on C4D2, followed by a ramp-up to a 400-mg dose once daily.

The primary end point assessment was taken on C16D1. For patients who achieved a BM uMRD and a complete response (CR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria, therapy was discontinued. Patients with a partial response (PR) would continue treatment with 9 cycles of acalabrutinib and venetoclax. A second assessment took place on C25D1. If a patient had BM uMRD, therapy was discontinued, otherwise acalabrutinib and venetoclax were continued until progression or toxicity.

Patients were eligible for enrollment if they had a confirmed diagnosis of previously untreated CLL/small lymphocytic leukemia, or B-cell prolymphocytic leukemia, and an ECOG Performance Status Scale score of 2 or less.

“The hematologic criteria were relatively permissive and patients also needed [to have] adequate hepatic and renal function,” Coombs said. “For the expansion cohort, patients needed to have TP53-aberrant disease.” The primary end point was the rate of achievement of uMRD CR determined by multicolor flow cytometry at 10-4.

For both the initial and expansion cohorts (n = 68), patients had a median age of 63 years (range, 36-80); the tumors of 41 patients (60.3%) harbored del(17p) and/or TP53 mutation, and the majority of patients (n = 50) had IgHV-unmutated status. Investigators noted the presence of complex karyotype of 3 or greater cytogenetic abnormalities in 26.2% of patients.

Among all patients, investigators reported an overall response rate of 98%, with a CR of 48% and PR of 50%. “When responses are broken up by TP53–wild type or TP53-aberrant disease, in the wild type population, the CR was 44% and the PR was 52%,” Coombs said. “Looking at patients with TP53-aberrant disease, CR was 52% and the PR was 48%. The proportion of CRs is relatively similar for both groups.”

Turning to uMRD, the investigators noted high rates of PB (86%) and BM uMRD (86%) in all patients. When PB and BM are stratified by TP53 status, PB MRD for patients with TP53–wild type disease had a uMRD rate of 85% vs those with TP53-mutant disease, with a uMRD rate of 86%. In BM MRD, TP53 wild type had a uMRD rate of 89% vs TP53 aberrant, which had a uMRD rate of 83%.

Regarding safety, the most common events that were grades 1 to 3 were headache (78%), fatigue (76%), and bruising (66%). “Safety is always a concern when using any triplet therapy,” Coombs said. “Fortunately, the majority of nonhematologic toxicities that occurred in more than 25% of patients were low-grade events.”

After a median follow-up of 35 months, the most common hematologic toxicity was neutropenia, with 37% of cases at grade 3 or 4 severity. Thrombocytopenia and anemia occurred in a reasonable subset of patients but did not lead to discontinuations, said Coombs. Looking at adverse events of special interest, Coombs noted that 5.8% of patients developed grade 3 non–COVID-19 infections and 9% of patients had COVID-19 infections. Three percent of patients developed atrial fibrillation although no ventricular arrhythmias were reported. Similarly, investigators observed zero cases of febrile neutropenia or opportunistic infections and no bleeding events.

Overall, 14 patients (21%) required dose reductions: 3 patients who received acalabrutinib, 6 patients who received venetoclax, and 5 patients who received both.

Regarding elective treatment discontinuation, 43 patients who achieved BM uMRD halted treatment, with 21 patients in CR and 22 patients in either CR or PR discontinuing. The median time off therapy was 18.8 months (range, 0-30.4), and 4 patients who discontinued had a disease recurrence.

Investigators reported 4 progression events and 1 death due to COVID-19 pneumonia. At a median follow-up of 35 months, 92.6% of all patients are progression free and alive; further, 98.5% of all patients are alive.